New drugs

(Aust Prescr 1996;19:38-40)

Some of the views expressed in the following notes on newly approved products should be regarded as tentative, as there may have been limited published data and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. As a result of fuller experience, initial comments may need to be modified. The Committee is prepared to do this. Before new drugs are prescribed, the Committee believes it is important that full information is obtained either from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Docetaxel

Taxotere (Rhone-Poulenc Rorer)
vials containing 20 mg/0.5 mL and 80 mg/2 mL for dilution

Indication: cancer chemotherapy
The anticancer drug paclitaxel is derived from the bark of the pacific yew tree. Docetaxel is obtained from the young shoots of the tree. The two drugs have not been approved for identical indications, although they can both be used to treat metastatic breast cancer when previous therapy has been unsuccessful. Docetaxel is also approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer.

The drug is given as a one-hour infusion every 3 weeks. High intracellular concentrations are thought to result in disruption of the microtubular network which is essential for mitosis. The drug is metabolised and most of the metabolites are excreted in the faeces within 48 hours.

Docetaxel can be used to treat locally advanced or metastatic non-small cell lung cancer. In previously untreated patients, the response rate is 31% compared with 19% in patients who have received treatment with platinum. Unfortunately, survival is only likely to be increased by a few months, but this may be important in a disease with a very poor prognosis.

Patients with locally advanced or metastatic breast cancer who do not respond to anthracycline also have a poor prognosis. Approximately half these patients will respond to docetaxel. The median duration of response is 27 weeks.

Docetaxel is cytotoxic and has many adverse effects. A severe neutropenia occurs in 75% of patients and can lead to fatal infections. Most patients will lose their hair and over 60% will develop rashes. Fluid retention also occurs in more than 60% of patients. It may present as oedema or effusions and is cumulative in incidence and severity. The onset of this adverse effect may be delayed if the patient begins oral steroids before each treatment. This premedication may also reduce the incidence and severity of the hypersensitivity reactions which occur in over 30% of patients.

As paclitaxel is a very expensive drug (over $1300 for 150 mg), the results of a comparative study of paclitaxel and docetaxel will be welcome.

Mivacurium chloride

Mivacron (GlaxoWellcome)
2 mg/mL in 5 mL, 10 mL and 25 mL ampoules

Indication: muscle relaxation
Intubation in general anaesthesia requires muscle relaxation. This can be achieved by antagonising the action of acetylcholine to block neuromuscular transmission. Mivacurium is a non -depolarising neuromuscular blocker which binds competitively to cholinergic receptors on the motor end-plate. It is a mixture of 3 stereoisomers and has a structure similar to atracurium.

Within a few minutes of intravenous injection, maximum blockade is achieved. However, mivacurium has a shorter duration of action than other non-depolarising neuromuscular blocking drugs. This means that the patient quickly recovers and may not require a reversal drug e.g. neostigmine.

To maintain neuromuscular block, mivacurium can be given by continuous infusion. The rate of infusion is adjusted at intervals of at least 3 minutes according to the clinical response. The half-life is less than two minutes with the termination of the blockade depending on hydrolysis by pseudocholinesterase.

Mivacurium activity is influenced by some disease states, e.g. hepatic dysfunction, and other drugs. The neuromuscular block can be potentiated by inhaled anaesthetics such as halothane. It is also increased by diuretics, propranolol, lignocaine, calcium channel blockers and some antibiotics.

Like atracurium, mivacurium can provoke the release of histamine from mast cells. Although hypotension and bronchospasm can be precipitated, flushing is more commonly observed, occurring in 15% of patients.

Perhexiline maleate

Pexid (Sigma Pharmaceuticals)
100 mg tablets

Indication: angina
This drug was introduced to Australia in 1978 (see 'New drugs' Aust Prescr 1978;2:108), but has not been generally available for a few years. The product is being reintroduced for patients who have contraindications, or have not responded to, other treatments for angina. As perhexiline has serious adverse effects, its use will be restricted to reducing the frequency of attacks in patients who have intractable angina, but cannot have coronary bypass surgery.

Adverse effects occur in 65% of patients and approximately 8% have to stop treatment. The severe adverse effects are peripheral neuropathy, papilloedema, hypoglycaemia and weight loss. Changes in liver enzymes occur frequently and some patients develop liver damage which can be fatal. All patients should be examined monthly and have regular monitoring of plasma concentrations, glucose and liver function.

Ropivacaine hydrochloride

Naropin (Astra Pharmaceuticals)
ampoules containing 2 mg/mL, 7.5 mg/mL and 10 mg/mL
2 mg/mL in 100 mL and 200 mL infusion bags

Indication: anaesthesia
Ropivacaine is a local anaesthetic with a similar structure to bupivacaine. The drug has been approved for epidural blocks, field blocks and major nerve blocks. It can be used in surgery, during labour and for postoperative pain.

At high doses, ropivacaine produces surgical anaesthesia, while lower doses cause a sensory block. These effects begin within a few minutes and last for 2-6 hours when ropivacaine is used for field blocks. The onset is similar when the drug is used for lumbar epidural anaesthesia, but the duration is shorter. Ropivacaine is extensively metabolised, so it is not recommended for patients with hepatic dysfunction.

The adverse effects of ropivacaine are similar to those of bupivacaine and include hypotension, bradycardia, nausea and vomiting. There is some evidence from animal studies that ropivacaine has less central nervous system and cardiovascular toxicity than bupivacaine. Acute systemic toxicity can cause convulsions, apnoea and cardiac arrest.

Sevoflurane

SEVOrane (Abbott Australasia)
250 mL bottles

Indication: anaesthesia
When given by vaporisation, sevoflurane liquid has anaesthetic effects. Its mechanism of action is probably similar to that of other inhaled anaesthetics such as halothane or isoflurane.

Sevoflurane is not pungent, so it can be used for inhalation induction e.g. in children. Anaesthesia can be achieved within two minutes. The minimum alveolar concentration (MAC) which results in 50% of patients not responding to a skin incision decreases with age. The MAC is also reduced by giving sevoflurane with nitrous oxide.

The drug is eliminated by exhalation. Adults usually emerge from anaesthesia in 8 minutes, slightly faster than with isoflurane.

Approximately 5% of the sevoflurane absorbed is metabolised. This results in the release of inorganic fluoride with concentrations usually peaking within two hours, but taking up to two days to return to baseline. This may potentially reduce the urine concentrating power of the kidneys. Metabolism does not produce trifluoracetic acid, which may be responsible for the adverse effects of halothane on the liver.

A degradation product (Compound A) results from sevoflurane coming into contact with CO2 absorbants in the anaesthetic circuit. Although Compound A may not reach concentrations that are deleterious to humans, it is nephrotoxic in rats. Sevoflurane is contraindicated in anaesthetic equipment employing rebreathing circuits which contain Baralyme.

Like other inhaled anaesthetics, sevoflurane causes cardiorespiratory depression; hypotension and bradycardia occur commonly. Other frequent adverse effects include agitation, breath-holding and laryngospasm during induction, and coughing, nausea and vomiting during recovery. Malignant hyperthermia may be triggered in susceptible patients.

Sevoflurane reacts with other drugs used in anaesthesia e.g. neuromuscular blocking agents and opioids. Dose adjustments are required.

At present, it is not clear if sevoflurane is any better overall than similar anaesthetic drugs.

Zuclopenthixol acetate

Clopixol-Acuphase (Lundbeck Australia)
50 mg/mL intramuscular injection in 1mL and 2 mL ampoules

Indication: psychoses
Thioxanthines are antipsychotic drugs with a similar structure to the phenothiazines. The more potent phenothiazines, e.g. fluphenazine, have a piperazine group added to the molecule; zuclopenthixol is a thioxanthine with a piperazine substitution. Thioxanthines have been used in schizophrenia and the manic phase of manic depressive illness as they block D1 and D2 dopamine receptors.

This formulation of zuclopenthixol is indicated for the treatment of acute psychoses, mania or exacerbations of chronic psychoses. An intramuscular injection takes 36 hours to produce a maximum serum concentration. The concentration falls by approximately 60% over 3 days so the injection can be repeated after 2 or 3 days if needed. The duration of treatment should not exceed two weeks and the total course should not exceed 4 injections or 400 mg.

Zuclopenthixol is probably as effective as similar antipsychotics and the adverse reaction profile is also similar. The most common adverse effects are extrapyramidal symptoms and drowsiness.

NEW FORMULATIONS

Baclofen

Lioresal Intrathecal (Ciba-Geigy)
0.05 mg/mL, 0.5 mg/mL and 2 mg/mL in 1 mL, 20 mL and 5 mL ampoules

Calcitriol

Calcijex (Abbott Australasia)
1 microgram/mL and 2 microgram/mL in 1 mL ampoules

Ganciclovir

Cymevene (Roche Products)
250 mg capsules

Ketoprofen

Orudis (Rhone-Poulenc Rorer)
25 mg tablets

Tretinoin

Vesanoid (Roche Products) 10 mg capsules

Indication: promyelocytic leukaemia
Tretinoin is a retinoid closely related to vitamin A. It is known to increase the proliferation of epidermal cells and so has been used for the treatment of acne. In vitro it can also induce the differentiation of leukaemic cells.

Promyelocytic leukaemia is associated with a translocation on chromosome 17. This translocation is in the region of a retinoic acid receptor, which may be the target for tretinoin. As conventional chemotherapy for this acute leukaemia has a high mortality and morbidity, tretinoin offers an alternative.

The drug is given twice a day for 30-90 days. This will induce remission in a majority of patients. After complete remission, a course of consolidation chemotherapy should be given.

Although the mortality associated with tretinoin may be less than for conventional treatment, it can cause serious adverse effects. Up to a quarter of patients may develop a hyperleucocytosis syndrome. The syndrome can present with fever and dyspnoea. There may be pleural effusions, pulmonary infiltrates, hypotension and respiratory failure. The syndrome can be fatal, but will often respond to high doses of steroids. Other adverse effects include rashes, oedema, hearing disorders, bone pain, nausea and vomiting.

Tretinoin is effective at inducing complete remissions in promyelocytic leukaemia, but its effect is short-lived. At present, it is uncertain if a better outcome is achieved by giving chemotherapy after tretinoin or giving the drugs concurrently.

NEW STRENGTHS

Desmopressin acetate

Octostim (Fisons Pharmaceuticals)
15 microgram/mL in 1 mL and 2 mL ampoules

Hepatitis A vaccine

Havrix 1440 (SmithKline Beecham)
1 mL vial containing 1440 ELISA units of hepatitis A virus antigen

Sumatriptan

Imigran (GlaxoWellcome)
50 mg tablets

NEW COMBINATIONS

Oestradiol and oestradiol/norethisterone acetate

Estracombi (Ciba-Geigy)
4 patches Estraderm 50 (50 micrograms oestradiol) and 4 patches Estragest (50 micrograms oestradiol with 250 micrograms norethisterone acetate)